The disease, diabetes mellitus, is recognized in two forms. Type I diabetes requires exogenous insulin for control of the disease because it appears that endogenous production of insulin by the Isles of Langerhans in the pancreas is extremely poor or non-existent. Type I diabetes is often referred to as insulin-dependent diabetes mellitus (IDDM). Type II, non-insulin-dependent diabetes mellitus (NIDDM), is characterized by defects of insulin sensitivity in peripheral tissues such as adipose tissue and muscle, as described by J. E. Gerich in New Engl. J. Med., 321, 1231-1245 (1989).
Hyperlipidemia is often observed in diabetics (Diabetes Care, 18, Supplement 1, 86-93, 1995). The combination of hyperlipidemia and hyperglycemia greatly increases the risk of cardiovascular diseases in diabetics. Successful treatment of hyperlipidemia and hyperglycemia in diabetics is needed urgently.
Blank reviewed hypoglycemic agents (Burger""s Medicinal Chemistry, 4th Ed., Part II, John Wiley and Sons, N.Y., 1979, 1057-1080). Newer hypoglycemic agents were reviewed by Hulin in Progress in Medicinal Chemistry, 31, ed. G. P. Ellis and D. K. Luscombe, Elsevier Publishing Co., 1993.
Currently, partial control of NIDDM is achieved by a diet and exercise regimen, by administration of exogenous insulin, by administration of hypoglycemic agents, (e.g. the sulfonylureas), or by some combination of these protocols. Sulfonylureas, such as chloropropamide, acetohexamide and tolbutamide, are useful orally-effective hypoglycemic agents achieving success in the control of NIDDM in numbers of patients. However, drugs currently available for the control of the hyperglycemia associated with type II diabetes mellitus (NIDDM) possess significant liabilities or limitations of efficacy. (Ellingboe, et al., J. Med. Chem. 36:2485-2493, 1993). Considerable effort has been expended toward developing novel, orally-administered antihyperglycemic drugs. A preferred therapeutic approach for treating NIDDM incorporates drugs that counteract insulin resistance rather than those that stimulate endogenous insulin secretion. (J. R. Colca and D. R. Morton, New Antidiabetic Drugs, ed. C. J. Bailey and P. R. Flatt, Smith-Gordon and Company, Ltd., London, Chapter 24, 1990). Drugs that treat insulin resistance are called insulin sensitivity enhancers.
Sato, Y, et al. (Diabetes Research and Clinical Practice, 12:53-60, 1991) described the hypoglycemic effect of D-phenylalanine derivatives. In normal dogs, the hypoglycemic activity of the compound was greater than that of tolbutamide but less than that of glibenclamide. The compounds exerted a rapid hypoglycemic effect and improved glucose tolerance in genetically diabetic KK mice and in streptozotocin-treated rats. Yamasaki, et al. disclosed a group of 2-quinolone derivatives showing antidiabetic activity in NIDDM (WO 92/21342).
Some known hypoglycemic compounds also reduce serum cholesterol or triglyceride levels. (Clark, et al., U.S. Pat. No. 5,036,079). The combination of these biological activities in one compound is particularly advantageous because diabetics are highly susceptible to hyperlipidemia. Hulin, in U.S. Pat. No. 5,306,726, claimed phenylpropionic acid derivatives and disclosed compounds that had hypoglycemic and hypocholesterolemic activity useful for the treatment of diabetes and atherosclerosis. Miyata, et al. found a class of phosphonic diester derivatives useful for treating diabetes and hyperlipidemia (WO 93/23409). Hypolipidemic amino acid derivatives were disclosed in JA-028189. Highly substituted aryl ethers of tyrosine were reported to have hypocholesterolemic activity (J. Med. Chem., 38:695-707, 1995). No aklyl ethers of tyrosine were disclosed.
This invention provides compounds of the Formula I 
wherein:
Q is selected from the group consisting of xe2x80x94(CH2)pxe2x80x94 and xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94;
R0 is selected from the group consisting of 
R2 is selected from the group consisting of C1-4 alkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, aryloxy C1-4 alkylcarbonyl, arylaminocarbonyl, aryl C1-4 acyl, aryl C1-4 alkoxycarbonyl, aryl C1-4 alkylaminocarbonyl, aryl C1-4 alkylsulfonyl and amino protecting groups;
R3 and R4 are independently hydrogen, or C1-4 alkyl;
R5 is xe2x80x94COOH, xe2x80x94CONR10R11, xe2x80x94CN, xe2x80x94CONHOH, or 
R6 is hydrogen, C1-4 alkyl, aryl, or aryl C1-4 alkyl;
R7 is hydrogen, halogen, or C1-4 alkyl;
R9 is hydrogen, C1-4 alkyl, or aryl;
R10 and R11 are independently hydrogen, C1-4 alkyl, or aryl;
W is xe2x80x94(CH2)nxe2x80x94;
Y is attached at position 3 or at position 4 of the ring, and is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94CONR9xe2x80x94, xe2x80x94NR9xe2x80x94SO2xe2x80x94, or xe2x80x94SO2xe2x80x94NR9xe2x80x94;
n is 1 to 4; and
p is 1, 2, or 3;
or a pharmaceutically-acceptable salt thereof; provided that when R6 is either hydrogen or C1-4 alkyl, then R7 is halogen, and that when p=1, then R0 is 
pharmaceutically acceptable salt thereof.
This invention also provides pharmaceutical formulations of the compounds of Formula I, and methods for treating hyperglycemia associated with non-insulin dependent diabetes and for treating hyperlipidemia by administering to a mammal an effective dose of a compound of the Formula I.
The terms used to describe the instant invention have the following meanings herein.
A xe2x80x9cmammalxe2x80x9d is an individual animal that is a member of the taxonomic class Mammalia. The class Mammalia includes humans, monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice, and rats.
xe2x80x9cHalogenxe2x80x9d refers to fluoro, chloro, bromo or iodo.
xe2x80x9cC1-4 alkylxe2x80x9d refers to straight or branched alkyl radicals having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and t-butyl.
xe2x80x9cC1-4 alkoxyxe2x80x9d refers to straight or branched chain alkyl radicals attached to oxygen having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, t-butoxy, and the like.
xe2x80x9cC1-4 alkylaminocarbonylxe2x80x9d refers to radicals of the formula: 
and includes, for example, methylaminocarbonyl, ethylaminocarbonyl, 2-propylaminocarbonyl, and the like.
xe2x80x9cArylxe2x80x9d refers to a substituted or unsubstituted aromatic radical selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl 3- thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl, 2-benzothieny, 3-benzothieny, 4-benzothieny, 5-benzothieny, 6-benzothieny, 7-benzothienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, and 8-indolyl. The optional substitutions of aryl may be at one or two carbon atoms of the aryl group, and may be with C1-4 alkyl, C1-4 alkoxy, halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94SO3H, xe2x80x94SO2NH2 or trifluoromethyl. Examples of substituted aryl groups are 4-methyl-3-furyl, 3,4-dimethyl-2-thienyl, 2,4-dimethyl-3-thienyl, 3-ethoxy-4-methyl-2-benzofuryl, 2-cyano-3-benzofuryl, 4-trifluoromethyl-2-benzothienyl, 2-chloro-3-benzothienyl, 3,4-dichloro-2-pyridyl, 2-bromo-3-pyridyl, 2-fluoro-4-pyridyl, 4-fluoro-2-furyl, 2-carboxyphenyl, 4-carboxamidophenyl, 3-trifluoromethylphenyl, bromo-1-naphthyl, 2,3-dimethyl-1-naphthyl, 3-carboxy-2-naphthyl, 5-carboxy-8-chloro-1-naphthyl, 3-ethyl-2-furyl, 8-fluoro-2-naphthyl, 5-trifluoromethyl-2-naphthyl, 6-ethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl, 3-carboxy-2-naphthyl, and the like.
xe2x80x9cArylcarbonylxe2x80x9d refers to radicals of the formula: 
for example, phenylcarbonyl, 4-methyl-1-naphthylcarbonyl, 3-trifluoromethylphenylcarbonyl, and the like.
xe2x80x9cAryloxycarbonylxe2x80x9d refers to radicals of the formula: 
and includes, for example, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 3-benzofuryloxycarbonyl, 2-benzothienyloxycarbonyl, 3-benzothienyloxycarbonyl, 2-pyridyloxycarbonyl, 3-pyridyloxycarbonyl, 3-ethyl-2-furyloxycarbonyl, 8-fluoro-2-naphthyloxycarbonyl, and the like.
xe2x80x9cArylaminocarbonylxe2x80x9d refers to radicals of the formula: 
and includes, for example, phenylaminocarbonyl, 2-naphthylaminocarbonyl, 4-methyl-3-furylaminocarbonyl, 3,4-dimethyl-2-thienylaminocarbonyl, 2,4-dimethyl-3-thienylaminocarbonyl, 3-ethoxy-4-methyl-2-benzofurylaminocarbonyl, 2-cyano-3-benzofurylaminocarbonyl, 4-trifluoromethyl-2-benzothienylaminocarbonyl, 2-chloro-3-benzothienylaminocarbonyl, 3,4-dichloro-2-pyridylaminocarbonyl, 2-bromo-3-pyridylaminocarbonyl, 3-furylaminocarbonyl, 2-benzofurylaminocarbonyl, 4-pyridylaminocarbonyl, and the like.
xe2x80x9cAryl C1-4 acylxe2x80x9d refers to radicals of the formula: 
and includes, for example, para-trifluoromethylbenzylcarbonyl, phenylacetyl, 2-(1-naphthyl)ethylcarbonyl, 2-phenylethylcarbonyl, 2-(3-benzofuryl)ethylcarbonyl, 2-furylacetyl, and the like.
xe2x80x9cAryl C1-4 alkyloxycarbonylxe2x80x9d refers to radicals of the formula: 
and includes, for example, benzyloxycarbonyl, 2-(2-naphthyl)ethoxycarbonyl, 6-phenylpropoxycarbonyl, 2-benzofurylmethoxycarbonyl, 3-chloro-4-methylbenzyloxycarbonyl, 4-carboxamidobenzyloxycarbonyl, and the like.
xe2x80x9cAryloxy C1-4 alkylcarbonylxe2x80x9d refers to radicals of the formula: 
and includes, for example, phenyloxymethylcarbonyl, 2-(2-indoyloxy)ethylcarbonyl, 3-(1-naphthyloxy)propylcarbonyl, 4-(3,5-dimethyl-4-pyridyloxy)butylcarbonyl, and the like.
xe2x80x9cAryl C1-4 alkylaminocarbonylxe2x80x9d refers to radicals of the formula: 
and includes, for example, phenylmethylaminocarbonyl, 2-(2-benzothienyl)propylaminocarbonyl, (2-naphthyl)methylaminocarbonyl, 2-thienylmethylaminocarbonyl, and the like.
xe2x80x9cAryl C1-4 alkylsufonylxe2x80x9d refers to radicals of the formula: 
and includes, for example, phenylmethylsulfonyl, and the like.
xe2x80x9cAryl C1-4 alkylxe2x80x9d refers to radicals of the formula: aryl-(C1-4 alkyl)-, and includes, for example, phenylmethyl, 2-(2-theinyl)ethyl, 3-(2-benzofuryl)propyl, benzyl, 4-chlorobenzyl, 3-ethyl-4-methylbenzyl, 3-chloro-4-methylbenzyl, 3,4-dichlorobenzyl, 3-isopropoxybenzyl, and the like.
The term xe2x80x9camino protecting groupxe2x80x9d as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the phtalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)iso-propoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcylcopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (xe2x80x9cFMOCxe2x80x9d), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-en-3-yloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, and the like; the benzoylmethylsulfonyl, the 2-(nitro)phenylsulfenyl group, the diphenylphosphine oxide group, and like amino protecting groups. The species of amino protecting group employed is not critical so long as the derivitized amino group is stable to the conditions of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Similar amino protecting groups used in the cephalosporin, penicillin, and peptide arts are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J. S. Barton, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, Chapter 7. The related term xe2x80x9cprotected aminoxe2x80x9d defines an amino group substituted with an amino protecting group discussed above.
The term xe2x80x9ccarboxy protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups of the compound. Examples of such carboxylic acid protecting groups include benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, pentamethylbenzyl, 3,4-methylenediozybenzyl, benzyhydryl, 4,4xe2x80x2-dimethoxybenzhydryl, 2,2,4,4xe2x80x2-tetramethoxybenzhydryl, t-butyl, isobutyl, n-butyl, propyl, isopropyl, ethyl, methyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenyacyl, 2,2,2-trichloroethyl, B-(trimethylsilyl)ethyl, B-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivitized carboxylic acid is stable to the conditions of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Carboxy protecting groups similar to those used in the cephalosporin, penicillin, and peptide arts can also be used to protect a carboxy group substituent of the compounds provided herein. Futher examples of these groups are found in E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1981, Chapter 5 and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 5.
The term xe2x80x9cxcex1 center amino acid protecting groupxe2x80x9d as used herein refers to a subset of amino protecting groups that are used to protect the amino group in addition to a hydrogen alpha to the amino group from base promoted racemization. Examples of such groups include the trityl group [Cherney, R. J. and Wang, L., J. Org. Chem. 61:2544 (1996); Christie, B. D.; Rapoport, H., J. Org. Chem. 50:1239 (1985)] and the phenylfluorenyl group [Guthrie, R. D. and Nicolas, E. C., J. Am. Chem. Soc. 103:4638 (1981)].
The term xe2x80x9chydroxy activation agentxe2x80x9d refers to organic or inorganic acids, acid halides, and acid anhydrides that are capable of converting a hydroxyl group into a leaving group labile to base treatment or nucleophilic displacement. Typical hydroxy activation agents include, but are not limited to sulfonating agents such as, methane sulfonyl chloride, p-toluenesulfonyl chloride, phenylsulfonyl chloride, trifluoromethylsulfonyl chloride, and the like, acylating agents such as isobutyl chloroformate, acetyl chloride, and the like, and halogenating reagents such as thionyl chloride, phosphorus tribromide, and the like.
The term xe2x80x9cactivated hydroxy groupxe2x80x9d refers to the moiety that results when a compound containing a hydroxy group is reacted with a hydroxy activating reagent e.g. the transformation from Oxe2x80x94H to O-methylsulfonyl, O-p-tolunesulfonyl, O-phenylsulfonyl, O-trifluoromethylsulfonyl, O-isobutylacetyl, O-acetyl, chloro, or bromo.
xe2x80x9cPharmaceutically-acceptable saltxe2x80x9d refers to salts of the compounds of the Formula I which are substantially non-toxic to mammals. Typical pharmaceutically-acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively. It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmaceutically-acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
Acids commonly employed to form acid addition salts are inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxides, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like. Examples of inorganic bases include, without limitation, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
Examples of such pharmaceutically-acceptable salts are, without limitation, the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex3-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like salts of the compound of Formula I. The preferred acid addition salts are those formed with mineral acids, such as, without limitation, hydrochloric acid, and hydrobromic acid, and those formed with organic acids, such as, without limitation, maleic acid and methanesulfonic acid. The potassium and sodium salt forms are particularly preferred base addition salts.
xe2x80x9cPharmaceutically-effective amountxe2x80x9d means that amount of a compound that will elicit the biological or medical response of a tissue, system, or mammal that is being sought by a researcher or clinician.
The geometric property that is responsible for the nonidentity of an object with its mirror image is called chirality. A compound that having a single chiral center may exist in either of two forms that are mirror images of each other. xe2x80x9cEnantiomerxe2x80x9d usually designates one of the two forms of such a compound. Enantiomer may also designate a homochiral collection molecules of a compound, or a heterochiral collection of molecules of a compound that contains an excess of one enantiomer over the other enantiomer. Absolute structural configuration of enantiomers of a chiral compound is designated by the letters xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d, using the rules of R. S. Cahn, C. K. Ingold, and V. Prelog in Agnew. Chem., 78:413 (1966); Agnew. Chem. Int. Ed., 5:385 (1966). An equimolar mixture of two enantiomers whose physical state is unspecified is called a xe2x80x9cracematexe2x80x9d. The adjectival form is xe2x80x9cracemicxe2x80x9d, as in xe2x80x9cracemic substance.xe2x80x9d The term xe2x80x9cracematexe2x80x9d includes within it xe2x80x9ccrystalline racematexe2x80x9d, which may refer to a conglomerate, a racemic mixture, a racemic compound, or a pseudoracemate [J. Jacques, A. Collet, and S. H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger Publ. Co., Malabar, Fla., 1991, pp. 4-5]. The asymmetric carbon atom at the position denoted by the star (*) creates the chirality of the compounds of Formula (I). 
It will be understood that preferred groups listed immediately below can be combined to create further, more narrowly limited groups of compounds. Preferred compounds are those wherein:
Q is xe2x80x94(CH2)pxe2x80x94;
Q is xe2x80x94(CH2)xe2x80x94;
Q is xe2x80x94(CH2)2xe2x80x94;
Q is xe2x80x94(CH2)3xe2x80x94;
p is 1;
p is 2 or 3;
Q is xe2x80x94CH2xe2x80x94Qxe2x80x94CH2xe2x80x94;
R0 is selected from the group consisting of 
R0 
R0 
R0 
R2 is arylcarbonyl, aryloxycarbonyl, arylaminocarbonyl, aryl C1-4 alkyloxycarbonyl, aryloxy C1-4 alkylcarbonyl, or aryl C1-4 alkylsulfonyl;
R2 is arylcarbonyl, aryloxycarbonyl, aryl C1-4 alkyloxycarbonyl, aryloxy C1-4 alkylcarbonyl, or aryl C1-4 alkylsulfonyl;
R2 is arylcarbonyl, aryloxycarbonyl, or aryl C1-4 alkyloxycarbonyl;
R2 is arylcarbonyl;
R2 is aryloxycarbonyl
R2 is arylaminocarbonyl;
R2 is aryl C1-4 alkyloxycarbonyl;
R2 is aryloxy C1-4 alkylcarbonyl;
R2 is aryl C1-4 alkylsulfonyl;
R2 is benzyloxycarbonyl, phenylcarbonyl, benzylcarbonyl, methylbenzylcarbonyl, phenyloxycarbonyl, para-chlorophenylcarbonyl, benzylsulfonyl, para-bromophenyloxycarbonyl, para-trifluoromethylphenyloxycarbonyl, para-methoxyphenyloxycarbonyl, para-n-butylphenyloxycarbonyl, or phenyloxymethylcarbonyl, benzylaminocarbonyl;
R3 is hydrogen;
R3 is methyl;
R3 is ethyl;
R3 is n-propyl or iso-propyl;
R3 is n-butyl, sec-butyl, or tert-butyl;
R4 is hydrogen;
R4 is methyl;
R5 is xe2x80x94COOH;
R5 is xe2x80x94CONR10R11;
R5 is 
R6 is aryl;
R6 is aryl C1-4 alkyl;
R6 is aryl methyl;
R6 is phenyl;
R6 is benzyl;
R7 is hydrogen;
R7 is halogen;
R7 is C1-4 alkyl;
R7 is fluorine;
R7 is methyl;
R9 is hydrogen;
R9 is C1-4 alkyl;
R9 is methyl;
R10 and R11 are independently hydrogen or C1-4 alkyl;
R10 and R11 are independently hydrogen;
R10 and R11 are independently C1-4 alkyl;
W is xe2x80x94(CH2)xe2x80x94;
W is xe2x80x94(CH2)2xe2x80x94;
W is xe2x80x94(CH2)3xe2x80x94;
W is xe2x80x94(CH2)4xe2x80x94;
Y is attached at position 3;
Y is attached at position 4;
Y is xe2x80x94Oxe2x80x94;
Y is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, or xe2x80x94SO2xe2x80x94;
Y is xe2x80x94Sxe2x80x94;
Y is xe2x80x94CONR9xe2x80x94, xe2x80x94NR9xe2x80x94SO2xe2x80x94, or xe2x80x94SO2xe2x80x94NR9xe2x80x94;
Y is xe2x80x94SO2xe2x80x94, xe2x80x94NR9xe2x80x94SO2xe2x80x94, or xe2x80x94SO2xe2x80x94NR9xe2x80x94;
n is 1;
n is 2;
n is 3;
n is 4;
the compound is the R enantiomer;
the compound is the S enantiomer;
the compound is the racemate.
It likewise will be understood that the particularly preferred groups listed immediately below can be combined to create further, more narrowly limited groups of compounds. Particularly preferred compounds are those wherein:
Q is xe2x80x94(CH2)pxe2x80x94;
Q is xe2x80x94(CH2)xe2x80x94;
p is 1;
Q is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94;
R0 is 
R2 is arylcarbonyl;
R2 is aryloxycarbonyl
R2 is aryl C1-4 alkyloxycarbonyl;
R2 is benzyloxycarbonyl, phenylcarbonyl, benzylcarbonyl, methylbenzylcarbonyl, phenyloxycarbonyl, para-chlorophenylcarbonyl, benzylsulfonyl, para-bromophenyloxycarbonyl, para-trifluoromethylphenyloxycarbonyl, para-methoxyphenyloxycarbonyl, para-n-butylphenyloxycarbonyl, or phenyloxymethylcarbonyl, benzylaminocarbonyl;
R3 is hydrogen;
R5 is xe2x80x94COOH;
R6 is aryl;
R6 is phenyl;
R7 is hydrogen;
W is xe2x80x94(CH2)2xe2x80x94;
Y is attached at position 3;
Y is attached at position 4;
Y is xe2x80x94Oxe2x80x94;
Y is xe2x80x94Sxe2x80x94;
n is 2
the compound is the R enantiomer;
the compound is the S enantiomer.
Further preferred compounds of Formula (I) are those wherein:
R0 is 
R2 is arylcarbonyl, aryloxycarbonyl,
arylaminocarbonyl, aryl C1-4 alkyloxycarbonyl,
aryloxy C1-4 alkylcarbonyl, or aryl C1-4 alkylsulfonyl;
R3 is hydrogen or methyl;
R4 is hydrogen or methyl;
R5 is xe2x80x94COOH, xe2x80x94CONR10R11, or 
R6 is aryl;
R7 is hydrogen, halogen, or methyl;
R10 and R11 are hydrogen;
Y is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
the compound is the R enantiomer;
the compound is the S enantiomer; and
the compound is the racemate.
More preferred compounds of Formula I are those wherein:
R0 is 
R2 is arylcarbonyl, aryloxycarbonyl, aryl C1-4 alkyloxycarbonyl, or aryl C1 4 alkylsulfonyl;
R5 is xe2x80x94COOH;
R7 is hydrogen, fluoro, or methyl;
Y is xe2x80x94Oxe2x80x94; and
n is 1 or 2.
Particularly preferred compounds of Formula I are those wherein:
Q is xe2x80x94(CH2)xe2x80x94or xe2x80x94(CH2)xe2x80x94Oxe2x80x94(CH2)xe2x80x94;
R0 is 
R2 is benzyloxycarbonyl, phenylcarbonyl, benzylcarbonyl, methylbenzylcarbonyl, phenyloxycarbonyl, para-chlorophenylcarbonyl, benzylsulfonyl, para-bromophenyloxycarbonyl, para-trifluoromethylphenyloxycarbonyl, para-methoxyphenyloxycarbonyl, para-n-butylphenyloxycarbonyl, or phenyloxymethylcarbonyl, benzylaminocarbonyl;
R6 is phenyl;
R7 is hydrogen;
Y is attached at the 3 position;
Y is attached at the 4 position; and
n is 2.
Preferred aryl radicals include phenyl, 1-naphthyl, and 2-naphthyl, optionally substituted with C1-4 alkyl, C1-4 alkoxy, halogen, xe2x80x94NO2, or triflurormethyl. A more preferred aryl radical is phenyl, optionally substituted with C1-4 alkyl, C1-4 alkoxy, halogen, xe2x80x94NO2, or triflurormethyl. A particularly preferred aryl radical is phenyl, optionally substituted at the para-position with methyl, ethyl, n-propyl, n-butyl, methoxy, fluoro, chloro, bromo, or trifluoromethyl.
A few compounds of this invention will be specifically mentioned to assure the reader""s comprehension. This invention includes both racemates, and individual enantiomers.
4-(2-naphthylmethylsulfonyl)benzyl-N-ethoxycarbonyl-serine-carbonitrile;
O-(2-(2-(2-naphthyl)-5-fluoro-4-thiazolyl)propyl)-N-benzoxycabonyl-tyrosine, free acid;
O-(3-(2-(2-flurorphenyl)ethylsulfinyl)benzyl)-N-benzoxycabonyl-serine, free acid;
O-(2-(methyl-2-pyridylamino)ethyl)-N-benzoxycabonyl-tyrosine, free acid;
O-(2-(2-benzoxazolylmethylamino)ethyl)-N-benzoxycabonyl-tyrosine, calcium salt;
O-(4-(4-(methyl-2-pyridylamino) butylaminosulfonyl)benzyl)-N-benzoxycabonyl-serine, free acid;
O-(4-(3-(2-benzoxazolylmethylamino)propylcarbonylamino)benzyl)-N-benzoxycabonyl-serine, lithium salt;
O-[2-(2-phenyl-5-methyl-4-oxazolyl)ethyl]-N-benzyloxycarbonyl-tyrosine, free acid;
O-[2-(2-phenyl-4-oxazolyl)ethyl]-N-benzyloxycarbonyl-tyrosine, sodium salt;
xcex1-(3-[2-(4-(2-naphthyl)phenyl)ethylamino]benzyl)-N-benzyloxycarbonyl-glycine, potassium salt;
O-(4-[4-(2-(2-furyl)-5-methyl-4-thiazolyl)butylsulfoxyl]benzyl)-N-benzyloxycarbonyl-serine, free acid;
O-(3-[2-(6-(2-pyridyl)-2-naphthyl)ethylaminosulfonyl]benzyl])-N-benzyloxycarbonyl-serine, calcium acid; and
O-[4-(3-phenyl-2-pyridylamino)butyl]-N-benzylcarbonyl-tyrosine, lithium salt.
A series of Schemes is presented below to familiarize the reader with chemical reactions and intermediates in the synthesis of compounds of Formula I. All substituents previously defined have the same meanings in the Schemes below. The substituent xe2x80x9cRxe2x80x9d in the Schemes below represents a carboxyl-protecting group. The substituent xe2x80x9cXxe2x80x9d in the Schemes below represents leaving group, such as a halogen. 
As described below in Schemes 2-4, compounds of Formula (I) wherein R5 is xe2x80x94COOH may be formed from compounds of Formula II by deprotecting the carboxyl group, following methods described in Greene and Wuts, Chapter 5, and then, optionally, forming another of the substituents of R5. Compounds of Formula I wherein R2 is other than hydrogen may be formed from compounds of Formula VI by adding the desired R2 substituent at the nitrogen atom of the compound of Formula VI as described in Greene and Wuts, Chapter 7, or in Schemes 13 and 14 herein. Compounds of Formula I may also be formed by reacting a compound of Formula III with a compound of Formula VII, as elaborated in Schemes 5-9 herein. 
Compounds of Formula I wherein R5 is xe2x80x94COOH may be derived from compounds of Formula II by deprotecting the 3-carboxylic acid group using methods described in Greene and Wuts, Chapter 5. 
Optionally, a compound of Formula I wherein R5 is xe2x80x94CONH2, xe2x80x94CN, xe2x80x94CONHOH, or 
may be formed from compounds of Formula I wherein R5 is xe2x80x94COOH, or an ester of xe2x80x94COOH. A first step is to form the acyl halide of (I) by reacting (I) wherein R5 is xe2x80x94COOH with thionyl chloride, phosphorus pentachloride, or phosphorus tribromide. Reaction of the acyl halide of (I) with hydroxylamine yields (I) wherein R5 is xe2x80x94CONHOH (the hydroxamate) (March, Advanced Organic Chemistry, McGraw-Hill, New York, 1968, page 335). Alternatively, where the xe2x80x94COOH is esterified, the ester may be treated with hydroxylamine hydrochloride and base, such as, potassium carbonate. Reaction of the acyl halide of (I) with ammonia, a primary amine, or secondary amine yields (I) wherein R5 is xe2x80x94CONR9R10. (Sonntag, Chem. Rev. 52:258-294, 1953). 
Treatment of a compound of Formula I wherein R5 is xe2x80x94CONH2 with an efficient dehydrating agent, such as P2O5, POCl3, or SOCl3, and acetic anhydride will convert it to a compound of formula (I) wherein R5 is xe2x80x94CN (Ugi, et al., Angew. Chem. Intern. Ed. Engl. 4:472-484, 1965; also, March, pages 777-778). A compound of Formula I wherein R5 is 
is made from a compound of Formula I wherein R5 is xe2x80x94CN by reacting it with sodium azide in a solvent such as dimethylformamide at about 140 degrees Centigrade together with a tin reagent, such as tri-n-butyl tin azide (Encyclopedia of Reagents for Organic Synthesis, ed. by L. A. Paquette, J. H. Wiley and Sons, New York, 1995, vol. 7, pp. 5035-5037). 
Compounds of Formula II may be made by addition of a compound of Formula III to a compound of Formula IV. Substituent Z3 of (III) and substituent Z4 of (IV) are such that reaction of (III) and (IV) results in the formation of Y. Depending on the type of Y group sought, Z3 may be xe2x80x94OH, xe2x80x94SO2Cl, xe2x80x94X (halogen), xe2x80x94NHR9, or xe2x80x94COCl and Z4 may be xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, or xe2x80x94SO2Cl, for example. Scheme 5 shows the general reaction. Schemes 6-9 show the formation of specific Y groups. The table below shows the substituents Z3 and Z4 that might be selected for each group, Y. The particular selections of Z3 and Z4 are not meant to limit the groups that the skilled chemist might use to form Y of the compounds of Formula I.

Where Z3 is xe2x80x94OH, and Z4 is xe2x80x94OH, compounds of Formula II wherein Y is xe2x80x94Oxe2x80x94 are synthesized by a standard method, such as the Mitsunobu reaction (Synthesis, p. 1, 1981; Hughes, D. L., Organic Reactions 42:336, 1992; Bose, A. K., et al., J. Can. Chem. 62:2498, 1984), as further exemplified in Example 1. 
To obtain a thioether, wherein Y of (II) is xe2x80x94Sxe2x80x94, Z3 of (III) is xe2x80x94X (a halogen) and Z4 of (IV) is xe2x80x94SH (March, page 1171). The compound of Formula II wherein Y is xe2x80x94SOxe2x80x94 may be formed from the thioether by oxidation using one equivalent of hydrogen peroxide (March, page 887). The compound of Formula II wherein Y is xe2x80x94SO2xe2x80x94 may be formed from the thioether by further oxidation using two equivalents of hydrogen peroxide, or using potassium permanganate, or other oxidizing agents (March, page 887). 
A compound of Formula (II) wherein Y is xe2x80x94NR9SO2xe2x80x94 is formed by reaction of compound III wherein Z3 is xe2x80x94NHR9, and compound IV wherein Z4 is xe2x80x94SO2Cl (March, page 374). 
Where Z3 is xe2x80x94COX and Z4 is xe2x80x94NH2, compound (II) wherein Y is xe2x80x94CONHxe2x80x94, is formed by amidation of an acid chloride (March, page 335). Reaction of (III) wherein Z3 is xe2x80x94X with (IV) wherein Z4 is xe2x80x94NH2, under conditions favorable for alkylation of the amine as described by March, page 331, results in the synthesis of (II) wherein Y is xe2x80x94NHxe2x80x94. A compound of Formula II wherein Y is xe2x80x94SO2NHxe2x80x94 is formed by reaction between a compound of Formula III wherein Z3 is xe2x80x94SO2Cl and a compound of Formula IV wherein Z4 is xe2x80x94NHR9 (March, page 374). A compound of Formula II wherein Y is xe2x80x94SO2NR9xe2x80x94 or xe2x80x94CONR9xe2x80x94 may be subsequently formed using an alkyl halide (R9xe2x80x94X) (March, page 340). 
Compounds of Formula III are synthesized using known reactions (A. R. Katritsky, Handbook of Heterocyclic Chemistry, Pergamon Press, 1985). Compounds of Formula III wherein Z3 is xe2x80x94NHR9, xe2x80x94SO2Cl, or xe2x80x94X may be made from a compound of Formula III wherein Z3 is xe2x80x94OH (the alcohol). Where Z3 is xe2x80x94NHR9, the alcohol is converted to an amine, for example, by formation of a tosylate or mesylate followed by nucleophilic displacement with a substituted or unsubstituted amine (I. T. Harrison and S. Harrison, Compendium of Organic Synthetic Methods, Wiley-Interscience, New York, 1971, pp. 232, and 250-255). Where Z3 is xe2x80x94SO2Cl, the alcohol may be converted to a halide (March, p. 343), which on subsequent treatment with sodium bisulfite is converted to a sulfonic acid sodium salt (S. R. Sandler and W. Karo, Organic Functional Group Preparations, Academic Press, New York, 1968, p. 512). Treatment of the sulfonic acid sodium salt with chlorosulfonic acid, for example, then produces the sulfonyl chloride (Sandler and Karo, p, 517). Where Z3 is xe2x80x94X, the alcohol is treated with a halogen acid, or an inorganic acid halide (March, page 343). To make a compound of Formula III wherein Z3 is xe2x80x94COX, a compound of formula 
may be oxidized to an acid (Harrison and Harrison, pp. 26-30), from which the halide may be formed (Harrison and Harrison, pp. 18-22). 
Scheme 11 shows syntheses of various alcohols used as starting material in Scheme 10. Partial reduction of the acid, R0xe2x80x94COOH, to the aldehyde (Harrison and Harrison, pp. 132-137) followed by Wittig condensation (March, pp. 845-854), olefin reduction (Harrison and Harrison, pp. 198-202) and further reduction to the alcohol (Harrison and Harrison, pp. 76-78), with or without saponification, will produce R0xe2x80x94(CH2)nxe2x80x94OH, for n greater than 2. Full reduction of the acid R0xe2x80x94COOH, will produce R0xe2x80x94CH2xe2x80x94OH. The alcohol R0xe2x80x94CH2xe2x80x94OH may be homologated to R0xe2x80x94(CH2)2xe2x80x94OH by standard methods, such as, conversion to halide (March, p. 343), displacement with cyanide (Harrison and Harrison, pp. 468-470), hydrolysis of the resulting nitrile to a carboxylic acid (Harrison and Harrison, pp. 62-64), and reduction of the acid to the alcohol (Harrison and Harrison, pp. 76-78).
Where R0 is 
the intermediate of the form R0xe2x80x94(CH2)nxe2x80x94OH maybe synthesized following Cantello, et al., J. Med. Chem., 37:3977-3985, 1994.
Where R0 is 
the reactions of Scheme 11 are followed starting with readily-available carboxylic acid, aldehyde, or alcohol derivatives of R0. 
Scheme 12 demonstrates a method to form intermediate compounds of the form R0xe2x80x94COOH which are used in Scheme 11. Where R0 is oxazole the method of L. A. Paquette, Principles of Modern Heterocyclic Chemistry, W. A. Benjamin, 1968, page 191, may be followed. A substituted thiazole may be obtained using the same scheme, but substituting the corresponding thioamide, following Paquette, page 193. The pyridyl intermediate of form R0xe2x80x94COOH may be prepared by the method of E. H. Rood, ed., Chemistry of Carbon Compounds, Vol. IVA, Elsevier Publ. Co., 1957, page 557. 
A compound of Formula IV, wherein Z4 is xe2x80x94OH may be formed according to Scheme 15, below. The aromatic hydroxy group may be optionally transformed by known reactions to form other compounds of Formula IV, wherein Z4 is xe2x80x94SH, xe2x80x94NH3, or xe2x80x94SOCl2. For example, the amine derivative is formed using 4-chloro-2-phenylquinazoline (Fieser and Fieser, 4, 86). The compound of Formula IV wherein Z4 is xe2x80x94SH may be formed by treating a compound of Formula IV wherein Z4 is xe2x80x94OH with dimethylthiocarbamyl halide in the presence of hydroxide ion at elevated temperature using Newman""s method (Fieser and Fieser 4, 202). A compound of Formula IV wherein Z4 is xe2x80x94SO3 is formed from a compound of Formula IV wherein Z4 is xe2x80x94SH by oxidation. 
Reagents for attaching the substituent R2 may be prepared as shown in Scheme 14, or may be found in Greene and Wuts, Chapter 7. For example, where it is desired that R2 be a an aryl C1-4 alkyloxycarbonyl group, the synthesis of Scheme 14 could start with the corresponding aryl C0-3 alkyl acid. The acid could be reduced to the alcohol, and the alcohol reacted with phosgene and base, for example, to yield the corresponding oxycarbonyl chloride. Alternatively, the corresponding alcohol could serve as the starting point if it were available.
An acyl halide or an aryl acyl halide may be used to form the compound of Formula I wherein R2 is aryl C1-4 acyl. The acyl halide is formed from the acid by standard methods, such as reaction of the acid with thionyl chloride, phosphorus pentachloride, or phosphorus tribromide.
An isocyanate derivative may be used to form the compound of Formula I wherein R2 is C1-4 alkylaminocarbonyl, arylaminocarbonyl, or aryl C1-4 alkylaminocarbonyl. The isocyanate may be formed from the acid halide by reaction with sodium azide (Fieser and Fieser, 1, 1041).
A sulfonyl chloride reagent may be used to create the compound of Formula I wherein R2 is aryl C1-4 alkylsulfonyl. The sulfonyl chloride reagent may be formed from an acid by reducing the acid to an alcohol, and then following the sequence described in Scheme 14.
In Scheme 14, R1 is a group such that reaction between a compound at the right side of Scheme 13 and the nitrogen atom to which the group R2 is to be attached leaves a group defined as R2 attached to said nitrogen atom. The relation between the groups R1, R2, and the compound used to derivatize the nitrogen atom are shown for some representative groups in the table below.

The compound of Formula (IV), used as starting material in Scheme 13, wherein Q is xe2x80x94(CH2)pxe2x80x94 may be synthesized from 3- or 4-hydroxybenaldehyde using Wittig homologation (J. Chem. Soc. Perkin, 1:3099, 1979) either once, or successively, depending on the value of p, and then forming the amino acid with protected carboxylic acid and amino groups from the resulting aldehyde as described in Organic Synthesis Coll., 1:21.
The compound of Formula (IV) wherein Q is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 is made from 3- or 4-hydroxybenzaldehyde by reducing the aldehyde, forming 3- or 4-hydroxybenzylbromide from the alcohol, reacting the bromide with serine having its carboxyl and amino groups protected, and finally, removing the protecting groups.
Compounds of formula (IV) wherein Q is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 and Y is xe2x80x94Oxe2x80x94 may also be prepared as illustrated in Scheme 16 below where H.A.A. is a hydroxy activating agent, R8 is an activated hydroxy group, Pg is an xcex1 center amino acid protecting group, and R is a carboxy protecting group. 
For example, a hydroxy activating agent (H.A.A.) may be added to a compound of formula (XII), dissolved or suspended in a suitable organic solvent, to form a compound of (XIII), wherein R8 is an activated hydroxy group. Suitable organic solvents include, but are not limited to, chloroform, 1,2-dichloroethane, diethyl ether, acetonitrile, ethyl acetate, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, dimethylformamide, toluene, chlorobenzene, dimethylsulfoxide, mixtures thereof, and the like. Methylene chloride is typically the preferred solvent. The choice of hydroxy activating agents is not critical but methanesulfonyl chloride is preferred. When a sulfonating or acylating hydroxy activating reagent is used, the reaction is preferably run in the presence of a suitable base. Suitable bases include, but are not limited to, carbonates, bicarbonates, and hydroxides (e.g. lithium, sodium, or potassium carbonate, bicarbonate, or hydroxide), or trialkylamines. The preferred base is triethylamine. The hydroxy activating agent is typically employed in a molar excess. For example, a 1.1 to a 1.5 molar excess relative to the compound of formula I is usually employed. A 1.25 molar excess is typically preferred. The base is also typically employed in a molar excess. For example, a 1.2 to a 1.6 molar excess relative to the compound of formula I is generally employed. A 1.4 molar excess is typically preferred. The reaction is generally performed at a temperature from xe2x88x9250xc2x0 C. to ambient temperature but is preferably performed at about 5xc2x0 C. for from about 1 to 3 hours.
Compounds of formula (XIII) may then be reacted with commercially-available 4-hydroxybenzaldehyde or 3-hydroxybenzaldehyde, compounds of formula (XIV), in a suitable organic solvent in the presence of a suitable base, to form a substituted hydroybenzaldehyde, a compound of formula (XV), as shown in Scheme 16. Suitable organic solvents include those mentioned as suitable organic solvents above, but dimethylformamide is preferred. Suitable bases include those mentioned as suitable bases above, but cesium carbonate is preferred. The compound of formula (XIII) and the base are typically employed in a slight molar excess. For example, a 1.01 to a 1.25 molar excess relative to the hydroxybenzaldehyde compound, (XIV), is usually employed. A 1.1 molar excess is typically preferred. The reaction is generally performed at a temperature from ambient to about the reflux temperature of the solvent but is preferably performed at about 45xc2x0 C. for from about 5 to 12 hours.
The aldehyde moiety of compound of formula (XV) may be reduced to an alcohol moiety, as shown in Scheme 16. Methods for reducing aldehydes to their corresponding alcohols are found in Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, N.Y., 1989, pg. 527. Specifically, the substituted hydroxybenzaldehyde, dissolved or suspended in a suitable organic solvent, is treated with a reducing agent, to form a compound of formula (VIII). Suitable organic solvents include those mentioned as suitable organic solvents above, in addition to lower alcohols. Isopropanol is usually a convenient and preferred solvent. Sodium borohydride is typically a convenient and preferred reducing agent. The reducing agent is typically employed in a molar excess but the magnitude of the excess will vary with the reducing agent employed. For example, when sodium borohydride is the reducing agent a 1.5 to a 3 molar excess, relative to the compound of formula (XV) is generally employed. A 2 molar excess is typically preferred. The reaction is typically and preferably performed at ambient temperature for about 18 hours.
A compound of formula (IX) may be prepared from a compound of formula (VIII) by activating the hydroxy group in the same manner as described above. The preferred solvent is methylene chloride and the preferred hydroxy activating reagent is phosphorous tribromide. The skilled artisan will recognize that when a halogenating reagent is the hydroxy activating agent, the presence of a base may be required, depending on the agent used. The reaction is preferably run at about 5xc2x0 C. when adding the halogenating reagent and then at ambient temperature for about 2 hours.
Compounds of formula (XI) may be prepared from compounds of formula (IX) and a commercially-available amino and carboxy protected serine of formula (X). For example, a solution of a compound of formula (IX) in an organic solvent may be added to an alkaline aqueous solution of a compound of formula (X) in the presence of a phase transfer catalyst. Suitable organic solvents include chloroform, 1,2-dichloroethane, ethyl acetate, toluene, chlorobenzene, mixtures thereof, and the like. Methylene chloride is typically the preferred organic solvent. The choice of bases which make the aqueous phase alkaline is not critical but sodium hydroxide is preferred. The compound of formula (IX) is typically employed in a slight molar excess. For example, a 1.05 to a 1.25 molar excess relative to the compound of formula (X) is usually employed. A 1.1 molar excess is typically preferred. Choice of phase transfer catalysts is not critical but tetrabutylammonium bromide is preferred. The reaction is generally performed at a temperature from ambient to the reflux temperature of the solvent and is preferably performed at about 40xc2x0 C. for from about 12 to 36 hours, typically 24 hours. For further illustration see e.g. Palmer, M. J., et al, Synlett, 1994, 171. For alternate methods for producing compounds of formula (XI) from compounds of formula (IX) and (X) see e.g. Cherney, R. J.; Wang, L., J. Org. Chem. 61, 2544 (1996).
Methods for removing trityl or phenylfluorenyl amino protecting groups in compound (XI) may be found in T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, pgs. 366-367 and the Examples section which follows. Methods for removing carboxy protecting groups without affecting amino protecting groups may be found in the Greene reference at 224-276 or in the Examples section which follows. The conversion of free carboxyl groups to other substituents is described above in Scheme 3.
The compounds of the present invention can be administered in oral forms, such as, without limitation, tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous (bolus or infusion), intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skill in that art.
The dosage regimen utilizing the compounds of the present invention is selected by one of ordinary skill in the medical or veterinary arts, in view of a variety of factors, including, without limitation, the species, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed, and the like.
The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefor. In making the compositions of the present invention, the active ingredient may be admixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which it may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
For oral administration in the form of a tablet or capsule, the active ingredient may be combined with an oral, non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate, calcium phosphate, calcium sulfate, sodium carbonate, mannitol, sorbitol, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginic acid, and the like; and, optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.
In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the instant invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid formulations include suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
Preferably, the pharmaceutical formulation is in unit dosage form. A xe2x80x9cunit dosage formxe2x80x9d is a physically discrete unit containing a unit dose, suitable for administration in human subjects or other mammals. A unit dosage form can be a capsule or tablet, or a number of capsules or tablets. A xe2x80x9cunit dosexe2x80x9d is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more pharmaceutically-acceptable excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the recipient. The dosage will also depend on the route of administration.
The oral route is most preferred. Typical oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg per kg body weight per day (mg/kg/day) to about 50 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
Administration to a human is most preferred. The human to whom the compounds and formulations of the present invention are administered has a disease or condition in which control blood glucose levels are not adequately controlled without medical intervention, but wherein there is endogenous insulin present in the human""s blood. Non-insulin dependent diabetes mellitus (NIDDM) is a chronic disease or condition characterized by the presence of insulin in the blood, even at levels above normal, but resistance or lack of sensitivity to insulin action at the tissues. The compounds and formulations of the present invention are also useful to treat acute or transient disorders in insulin sensitivity, such as sometimes occur following surgery, trauma, myocardial infarction, and the like. The compounds and formulations of the present invention are also useful for lowering serum triglyceride levels. Elevated triglyceride level, whether caused by genetic predisposition or by a high fat diet, is a risk factor for the development of heart disease, stroke, and circulatory system disorders and diseases. The physician of ordinary skill will know how to identify humans who will benefit from administration of the compounds and formulations of the present invention.
The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxylmethyl starch, magnesium stearate, and talc, previously passed though a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
The active ingredient, starch, cellulose, and magnesium stearate are blended, the blend is passed through a No. 45 mesh U.S. sieve, and then hard gelatin capsules are filled with 200 mg of the blend.
The active compound is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides, previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
The active ingredient, starch, cellulose, and magnesium stearate are blended, the blend is passed through a No. 45 mesh U.S. sieve, and then hard gelatin capsules are filled with 200 mg of the blend.
The compound of the present invention is dissolved in the saline and administered intravenously at a rate of 1 mL per minute to a subject in need thereof.